7A-Homo-4-oxo-PGI1 compounds

ABSTRACT

This invention relates to certain 7a-homo-4-oxo-PGI 1  compounds. These novel prostacyclin-type compounds are useful for pharmacological purposes.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 857,106, filed Dec. 5, 1977, now U.S. Pat. No. 4,126,744.

The present invention relates to 7a-homo-4-oxo-PGI₁ compounds whose preparation and use is described in Ser. No. 857,106, filed Dec. 5, 1977, now issued as U.S. Pat. No. 4,126,744.

The essential material constituting a disclosure of these 7a-homo-4-oxo-PGI₁ compounds is incorporated here by reference from U.S. Pat. No. 4,126,744. 

I claim:
 1. A prostacyclin analog of the formula ##STR1## wherein ˜ represents attachment of the side chain in the alpha or beta configuration or a mixture of alpha and beta configurations;Wherein g is the integer one, 2, or 3; Where R₈ is hydrogen, hydroxy, or hydroxymethyl; Wherein Y₁ is (1) trans --CH═Ch--, (2) cis --CH═CH--, (3) --ch₂ ch₂ --, or (4) --C.tbd.C--,wherein M₁ is ##STR2## wherein R₅ is hydrogen or alkyl with one to 4 carbon atoms, inclusive, Wherein L₁ is ##STR3## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; Wherein Z₁ is (1) --COOR₁ wherein R₁ is hydrogen; alkyl of one to 12 carbon atoms, inclusive; cycloalkyl of 3 to 10 carbon atoms, inclusive; hydrocarbylaralkyl of 7 to 12 carbon atoms, inclusive; phenyl; phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms; phenyl substituted in the para position by ##STR4## WHEREIN R₂₅ is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH₂ ; R₂₆ is methyl, phenyl, --NH₂, or methoxy; and R₂₇ is hydrogen or acetamido; inclusive, phenacyl, i.e., ##STR5## phenacyl substituted in the para position by chloro, bromo, phenyl, or benzamido; of a pharmacologically acceptable cation; (2) --CH₂ OH; or (3) --COL₄, wherein L₄ is (a) amino of the formula --NR₂₁ R₂₂ ; wherein R₂₁ and R₂₂ are hydrogen; alkyl of one to 12 carbon atoms, inclusive; cycloalkyl of 3 to 10 carbon atoms, inclusive; aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; phenyl substituted with one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro; carboxyalkyl of one to 4 carbon atoms, inclusive; carbamoylalkyl of one to 4 carbon atoms, inclusive; cyanoalkyl of one to 4 carbon atoms, inclusive; acetylalkyl of one to 4 carbon atoms, inclusive; benzoylalkyl of one to 4 carbon atoms, inclusive; benzoylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbon atoms, inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive, or nitro; pyridyl; pyridyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms; inclusive; pyridylalkyl of one to 4 carbon atoms, inclusive; pyridylalkyl substituted by one, 2, or 3 chloro, alkyl of one to 3 carbon atoms, inclusive, hydroxy, or alkoxy of one to 3 carbon atoms, inclusive; hydroxyalkyl of one to 4 carbon atoms, inclusive; dihydroxyalkyl of one to 4 carbon atoms, and trihydroxyalkyl of one to 4 carbon atoms; with the further proviso that not more than one of R₂₁ and R₂₂ is other than hydrogen or alkyl; (b) cycloamino selected from the group consisting of ##STR6## wherein R₂₁ and R₂₂ are as defined above; (c) carbonylamino of the formula --NR₂₃ COR₂₁, wherein R₂₃ is hydrogen or alkyl of one to 4 carbon atoms and R₂₁ is as defined above; (d) sulfonylamino of the formula --NR₂₃ SO₂ R₂₁, wherein R₂₁ and R₂₃ are as defined above; or (e) hydrazino of the formula --NR₂₃ R₂₄, wherein R₂₃ is as defined above and R₂₄ is amino of the formula --NR₂₁ R₂₂, as defined above, or cycloamino, as defined above; andwherein R₇ is (1) --(CH₂)_(m) --CH₃, ##STR7## wherein m is the integer one to 5, inclusive, h is the integer zero to 3, inclusive; s is the integer zero, one, 2, or 3, and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two T's are other than alkyl.
 2. A prostacyclin analog according to claim 1, wherein R₈ is hydroxymethyl.
 3. 7a-Homo-11-deoxy-11α-hydroxymethyl-4-oxo-6α- or 6β-PGI₁, a prostacyclin analog according to claim
 2. 4. A prostacyclin analog according to claim 1, wherein R₈ is hydrogen.
 5. 7a-Homo-11-deoxy-4-oxo-6α- or 6β-PGI₁, a prostacyclin analog according to claim
 4. 6. A prostacyclin analog according to claim 1, wherein R₈ is hydroxy.
 7. A prostacyclin analog according to claim 6, wherein Y₁ is cis --CH═CH--, --C.tbd.C--, or --CH₂ CH₂ --.
 8. 7a-Homo-cis-13-4-oxo-PGI₁, a prostacyclin analog according to claim
 7. 9. 7a-Homo-13,14-Didehydro-4-oxo-6α- or 6β-PGI₁, a prostacyclin analog according to claim
 7. 10. 7a-Homo-13,14-Dihydro-4-oxo-6α- or 6β-PGI₁, a prostacyclin analog according to claim
 7. 11. A prostacyclin analog according to claim 6, wherein Y₁ is trans --CH═CH--,
 12. A prostacyclin analog according to claim 11, wherein the C-6 side chain is a mixture of alpha and beta isomers.
 13. 7a-Homo-(6RS)-4-oxo-PGI₁, a prostacyclin analog according to claim
 1. 14. A prostacyclin analog according to claim 11, wherein the C-6 side chain is in the alpha configuration.
 15. 7a-Homo-4-oxo-6α-PGI₁, a prostacyclin analog according to claim
 14. 16. A prostacyclin analog according to claim 11, wherein the C-6 side chain is in the beta configuration.
 17. A prostacyclin analog according to claim 16, wherein g is two.
 18. 2a,7a-Dihomo-4-oxo-6β-PGI₁, a prostacyclin analog according to claim
 17. 19. A prostacyclin analog according to claim 16, wherein g is one or
 3. 20. A prostacyclin analog according to claim 19, wherein g is one.
 21. A prostacyclin analog according to claim 20, wherein R₇ is ##STR8##
 22. 7a-Homo-17-phenyl-18,19,20-trinor-4-oxo-6β-PGI₁, a prostacyclin analog according to claim
 21. 23. A prostacyclin analog according to claim 20, wherein R₇ is ##STR9##
 24. 7a-Homo-16-phenoxy-17,18,19,20-tetranor-4-oxo-6β-PGI₁, a prostacyclin analog according to claim
 23. 25. A prostacyclin analog according to claim 20, wherein R₇ is --(CH₂)_(m) --CH₃ --.
 26. A prostacyclin analog according to claim 25, wherein m is
 3. 27. A prostacyclin analog according to claim 26, wherein X₁ is --COL₄.
 28. 7a-Homo-4-oxo-6β-PGI₁, amide, a prostacyclin analog according to claim
 27. 29. A prostacyclin analog according to claim 27, wherein X₁ is --CH₂ OH.
 30. 7a-Homo-2-decarboxy-2-hydroxymethyl-4-oxo-6β-PGI₁, a prostacyclin analog according to claim
 29. 31. A prostacyclin analog according to claim 26, wherein X₁ is --COOR₁.
 32. A prostacyclin analog according to claim 31, wherein R₅ is methyl.
 33. 7a-Homo-15-methyl-4-oxo-6β-PGI₁, a prostacyclin analog according to claim
 32. 34. A prostacyclin analog according to claim 31, wherein R₅ is hydrogen.
 35. A prostacyclin analog according to claim 34, wherein at least one of R₃ and R₄ is fluoro.
 36. 7a-Homo-16,16-difluoro-4-oxo-6β-PGI₁, a prostacyclin analog according to claim
 35. 37. A prostacyclin analog according to claim 34, wherein at least one of R₃ and R₄ is methyl.
 38. 7a-Homo-16,16-dimethyl-4-oxo-6β-PGI₁, a prostacyclin analog according to claim
 37. 39. A prostacyclin analog according to claim 34, wherein R₃ and R₄ are both hydrogen.
 40. 7a-Homo-4-oxo-6β-PGI₁, methyl ester, a prostacyclin analog according to claim
 39. 41. 7a-Homo-4-oxo-6β-PGI₁, tris(hydroxymethyl)amino methane salt, a prostacyclin analog according to claim
 39. 42. 7a-Homo-4-oxo-6β-PGI₁, adamantanamine salt, a prostacyclin analog according to claim
 39. 43. 7a-Homo-4-oxo-6β-PGI₁, a prostacyclin analog according to claim
 39. 